中枢神経系疾患の治療は正常細胞（ニューロン）の機能維持を目的とするが，脳血管障害のように機能障害の原因が細胞の死滅に基づくことは多い．一方，脳腫瘍の治療においては薬物療法や放射線療法といった腫瘍細胞の死滅を目標とするものが大きな位置を占める．いずれの場合にも，細胞死の機序を理解することは各種病態や治療法の理解のうえで重要である．現在のところ最も研究の進んでいる細胞死の型はアポトーシスである．そのなかで重要な位置を占めるミトコンドリアにおける反応および抗アポトーシス因子について概要を紹介する．

Neuroscience 細胞死：最近の知見

В статье представлен материал о выдающемся русском ученом и общественном деятеле Сергее Сергеевиче Корсакове. Показана его роль в развитии отечественной психиатрии, в области профилактики психических болезней, проведении реформ в психиатрических учреждениях. Особое внимание уделено теме психического здоровья, раскрытой в трудах С. С. Корсакова.

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Тема психического здоровья в трудах С. С. Корсакова

Privileged structures have been widely used as an effective template for the research and discovery of high value chemicals. Coumarin is a simple scaffold widespread in Nature and it can be found in a considerable number of plants as well as in some fungi and bacteria. In the last years, these natural compounds have been gaining an increasing attention from the scientific community for their wide range of biological activities, mainly due to their ability to interact with diverse enzymes and receptors in living organisms. In addition, coumarin nucleus has proved to be easily synthetized and decorated, giving the possibility of designing new coumarin-based compounds and investigating their potential in the treatment of various diseases. The versatility of coumarin scaffold finds applications not only in medicinal chemistry but also in the agrochemical field as well as in the cosmetic and fragrances industry. This review is intended to be a critical overview on coumarins, comprehensive of natural sources, metabolites, biological evaluations and synthetic approaches.

An overview of coumarin as a versatile and readily accessible scaffold with broad-ranging biological activities

Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with abnormal protein modification, inflammation and memory impairment. Aggregated amyloid beta (Aβ) and phosphorylated tau proteins are medical diagnostic features. Loss of memory in AD has been associated with central cholinergic dysfunction in basal forebrain, from where the cholinergic circuitry projects to cerebral cortex and hippocampus. Various reports link AD progression with declining activity of cholinergic neurons in basal forebrain. The neurotrophic molecule, nerve growth factor (NGF), plays a major role in the maintenance of cholinergic neurons integrity and function, both during development and adulthood. Numerous studies have also shown that NGF contributes to the survival and regeneration of neurons during aging and in age-related diseases such as AD. Changes in neurotrophic signaling pathways are involved in the aging process and contribute to cholinergic and cognitive decline as observed in AD. Further, gradual dysregulation of neurotrophic factors like NGF and brain derived neurotrophic factor (BDNF) have been reported during AD development thus intensifying further research in targeting these factors as disease modifying therapies against AD. Today, there is no cure available for AD and the effects of the symptomatic treatment like cholinesterase inhibitors (ChEIs) and memantine are transient and moderate. Although many AD treatment studies are being carried out, there has not been any breakthrough and new therapies are thus highly needed. Long-term effective therapy for alleviating cognitive impairment is a major unmet need. Discussion and summarizing the new advancements of using NGF as a potential therapeutic implication in AD are important. In summary, the intent of this review is describing available experimental and clinical data related to AD therapy, priming to gain additional facts associated with the importance of NGF for AD treatment, and encapsulated cell biodelivery (ECB) as an efficient tool for NGF delivery.

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Innovative Therapy for Alzheimer's Disease-With Focus on Biodelivery of NGF.

Nanoparticles for brain-specific drug and genetic material delivery, imaging and diagnosis.

A large amount of clinical and experimental data suggest the involvement of neurotrophins, in particular the brain-derived neurotrophic factor (BDNF), in depression pathogenesis. However, the therapeutic use of BDNF is limited because of its instability in biological fluids, poor blood-brain barrier (BBB) permeability, and the presence of side effects. A low-molecular-weight mimetic GSB-106, which is a substituted dimeric dipeptide bis(N-monosuccinyl-L-seryl-L-lysine)hexamethylenediamide, was designed and synthesized based on the BDNF fourth loop structure at the V.V. Zakusov Institute of Pharmacology (RAMS). GSB-106 was found to exhibit an antidepressant activity in various models of depressive-like state when administered intraperitoneally to outbred mice and rats. An effect for the substance, when administered daily for 4-5 days, was detected in the Porsolt forced swimming test (0.1 and 1.0 mg/kg) and in the tail suspension test in mice (1.0 and 1.5 mg/ kg). An effect for GSB-106 at doses of 0.1 and 0.5 mg/kg was observed after a single application in experiments on rats in the Nomura water wheel test. The obtained evidence supports the hypothesis on the involvement of BDNF in the pathogenesis of various depression conditions, thus opening prospects for searching for new original antidepressants.

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Antidepressant Effect of Dimeric Dipeptide GSB-106, an Original Low-Molecular-Weight Mimetic of BDNF.

We present here the synthesis of 3- and 4-benzoylpyridine oxime derivatives with potential anticonvulsant action. The most active compound in the maximum electric shock test was 4-benzoylpyridine O-2-morpholinoethyloxime oxalate (1a), i.p. doses of 60 – 150 mg/kg of which increased the survival of mice to 100%. The best effect in the corasol antagonism test was obtained with 4-benzoylpyridine O-(isonicotinoyl)oxime (2c), i.p. doses of 12.5 mg/kg of which increased the survival of mice to 67% and the latent period of onset of generalized tonic-clonic convulsions to 52 sec. Compound 1a had low toxicity (the i.p. LD50 in mice was 316 mg/kg) and a therapeutic index of 21.

Synthesis and Anticonvulsive Activity of 3- and 4-Benzoylpyridine Oxime Derivatives

Human recombinant erythropoietin adsorbed on poly(butyl)cyanoacrylate nanoparticles and administered intraperitoneally in a dose of 0.05 mg/kg exhibited a neuroprotective effect in experimental intracerebral posttraumatic hematomas (hemorrhagic stroke) and reduced animal mortality. Human recombinant erythropoietin, native and adsorbed on lactic and glycolic acid copolymer-based nanoparticles, exhibited no antistroke effect on this model. Analysis of reverse transcription PCR products showed that human recombinant erythropoietin adsorbed on poly(butyl)cyanoacrylate nanoparticles more than 2-fold increased the expression of BDNF and NGF neurotrophins in the rat brain frontal cortex and hippocampus.

Involvement of BDNF and NGF in the Mechanism of Neuroprotective Effect of Human Recombinant Erythropoietin Nanoforms

Previously designed cyclo-L-prolylglycine (CPG), a peptide prototype of piracetam, was discovered as an endogenous compound in rat brain and exhibited nootropic and anxiolytic properties. N-Phenylacetylglycyl-L-proline ethyl ester (GZK-111) was synthesized in the present work. It was established that GZK-111 converted to CPG and possessed nootropic, anxiolytic, and antihypoxic activities typical of CPG at doses of 0.1 – 1.5 mg/kg (i.p.). The effects of both GZK-111 and CPG were stereoselective with only the L-enantiomers being active. GZK-111 could be considered as a prodrug that enhanced cognitive functioning with an anxiolytic component.

N -Phenylacetylglycyl- L -Proline Ethyl Ester Converts into Cyclo- L -Prolylglycine Showing a Similar Spectrum of Neuropsychotropic Activity

New dibenzofuranone-oxime derivatives were designed based on active structures of oxime esters. Compounds of the proposed group were synthesized using 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one oxime and aromatic acid chlorides. The anticonvulsant activity of the new compounds was studied. The structure— activity relationship was analyzed. Compound 1a [3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one O-(3,4-dichlorobenzoyl)oxime] was the most active compound after i.p. injection to mice in the maximal electroshock test over a wide dose range of 20 – 100 mg/kg. Compound 1a at doses of 10 and 30 mg/kg exhibited antihypoxic activity in a hypoxia test with hypercapnia in a hermetic chamber and anti-ischemic activity at a dose of 10 mg/kg in a rat ischemic stroke model.

S. A. Litvinova

Papers

Antidepressant Effect of Dimeric Dipeptide GSB-106, an Original Low-Molecular-Weight Mimetic of BDNF.

Synthesis and Anticonvulsive Activity of 3- and 4-Benzoylpyridine Oxime Derivatives

Involvement of BDNF and NGF in the Mechanism of Neuroprotective Effect of Human Recombinant Erythropoietin Nanoforms

N -Phenylacetylglycyl- L -Proline Ethyl Ester Converts into Cyclo- L -Prolylglycine Showing a Similar Spectrum of Neuropsychotropic Activity

Synthesis of Dibenzofuranone-Oxime Derivatives with Anticonvulsant, Antihypoxic, and Anti-Ischemic Activity